1. Field of the Invention
The present invention relates generally to red blood cells and the development of compounds which can be used to replace or supplement red blood cells. More particularly, the present invention relates to synthetic compounds which have the same oxygen transport capabilities as red blood cells and can be used in vivo and in vitro as a red blood cell surrogate.
2. Description of Related Art
There has been, and continued to be, a great deal of interest in developing suitable blood substitutes. One avenue of investigation involves the use of free hemoglobin solutions. However, free monomeric and polymeric as well as cross-linked hemoglobin solutions exhibit osmolarities which are much greater than normal blood. The high osmolarity tends to produce complications of vascular volume and perfusion pressures. Another problem is that unmodified hemoglobin is freely filtered at the glomerulus and is nephrotoxic.
The use of free hemoglobin in a blood substitute is further complicated by contaminants which may be present in the hemoglobin source or which may be introduced during the manufacturing process. Endotoxins and phospholipids are typical examples of contaminants which may be problematic in deploying hemoglobin solutions as blood substitutes. In addition, heterogenous sources of hemoglobin have been shown to produce marked antibody titers in rats. Also, immunogenic complications have also been reported in human trials.
Another approach to blood substitutes involves the use of perfluorocarbons. These blood substitutes typically contain from 10-20% perfluorocarbon by weight and contain particle sizes of approximately 150 nm. The perfluorocarbon type blood substitutes have been reported to have adequate oxygen delivery capacity. However, perfluorocarbons exhibit a linear oxygen dissociation curve which is not desirable for optimum oxygen transport. In addition, perfluorocarbons have several clinical complications. Perfluorocarbons are easily trapped in blood filter organs, resulting in depatomergaly and splenomegaly over a period of some weeks to months. Further, perfluorocarbons exhibit cytotoxic effects and are readily adsorbed by erythrocytes. This adsorption results in decreased cellular flexibility which could impair passage of the erythrocytes through capillary beds.
The encapsulation of hemoglobin in liposomes is another type of blood substitute which has been investigated. Liposome encapsulation of hemoglobin was first successfully used as a blood substitute about 40 years ago. At that time, hemoglobin was encapsulated in a collodion membrane. Liposome encapsulation has been successful in lowering the toxicity of biological agents and increasing their circulation time. Cholesterol, phosphatidylcholine and other lipids have been used to produce encapsulated hemoglobin capsules having diameters on the order of 200 to 500 microns.
Liposome encapsulated hemoglobin appears to overcome many of the complications presented by the use of perfluorocarbons and free hemoglobin. However, some clinical complications still exist. For example, problems with reticuloendothelial uptake, platelet aggregation and suppression of the reticuloendothelial system have been experienced. As is apparent, there presently is a continuing need to provide new synthetic compositions which can function effectively as a substitute for red blood cells. The synthetic composition must be capable of providing acceptable levels of oxygen transport without causing undesirable side effects. The synthetic material should be easily stored and have a reasonable shelf-life. The blood substitute should be amenable to use in a wide variety of situations including resuscitation in field trauma following massive blood loss or blood replacement during surgery. In addition, the blood substitute should be amenable to in vitro use to perfuse organs such as hearts, livers and kidneys during transport and transplantation.